BACKGROUND: Alzheimer's disease (AD) exhibits sex differences in prevalence, symptoms and risk factors. Understanding the effect of sex in AD cerebrospinal fluid (CSF) biomarkers and their association with amyloid-beta (Aβ) pathology in preclinical stages have important implications for their use in prevention trials. The objective of this study was to examine sex differences in core AD CSF biomarkers used in early diagnosis and prevention trials, as well as in CSF biomarkers reflecting downstream pathophysiological mechanisms, and in their associations with Aβ pathology as measured by Positron Emission Tomography (PET). METHODS: Cognitively Unimpaired (CU) participants from the ALFA + (N = 400) and the WRAP/WADRC (N = 548) cohorts were included in the study. CSF biomarkers for core AD pathology (Aβ42, Aβ42/40, p-tau181/Aβ42, p-tau181, p-tau217 and p-tau231), neurodegeneration (NfL, t-tau), synaptic dysfunction (neurogranin, GAP-43, SNAP25, synaptotagmin-1, α-synuclein), glial reactivity (GFAP, S100B, sTREM2, YKL-40), neuroinflammation (IL-6, MCP-1), and vascular dysregulation (sICAM-1, sVCAM-1) were measured. Participants underwent Aβ PET at baseline and follow-up visit. We used Analyses of Covariance (ANCOVA) to evaluate sex differences in CSF biomarker levels and performed sex-stratified Receiver-Operating Characteristic (ROC) analyses to test their performance to identify Aβ PET-positive individuals. Additionally, we run linear regression models to study the modifying effect of sex on the association of baseline CSF biomarkers with cross-sectional and longitudinal Aβ PET uptake. RESULTS: Men had higher CSF NfL, glial reactivity and vascular dysregulation biomarkers (Cohen's d ranging from -0.22 to -0.44, P < 0.05), and lower synaptic biomarkers (Cohen's d ranging from 0.18 to 0.30, P < 0.05) compared to women at baseline. There were no sex differences in the core AD CSF biomarkers' performance to identify Aβ PET-positive individuals (DeLong's test P values > 0.05), with CSF p-tau181/Aβ42 and p-tau217 showing the highest performance in both sexes (Areas Under the Curve (AUCs) ranging from 87.1 to 96.3). However, sex modified the associations of baseline CSF biomarkers with Aβ PET uptake, which were more pronounced in women than in men. CONCLUSIONS: Our results suggest that tailoring core AD CSF biomarkers by sex is not necessary for detecting Aβ PET positivity in CU individuals. However, sex differences in their association with Aβ deposition could influence their prognostic or monitoring applications.

Barcelona Supercomputing Center Life Sciences Department and Bioinfo4Women Barcelona Spain

Barcelonaβeta Brain Research Center Pasqual Maragall Foundation Barcelona Spain

Center for Alzheimer Research Karolinska Institute Solna Sweden

Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable Madrid Spain

Department of Health Sciences and Medicine University of Lucerne Lucerne Switzerland

Department of Radiology and Biomedical Imaging University of California San Francisco San Francisco CA USA

Global Brain Health Institute San Francisco CA USA

Hospital del Mar Research Institute Barcelona Spain

Memory Clinic Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Memory Clinic Krembil Brain Institute University Health Network Toronto ON Canada

Neurology Department Hospital del Mar Barcelona Spain

Northern California Institute for Research and Education San Francisco CA USA

Roche Diagnostics GmbH Penzberg Germany

Roche Diagnostics International Ltd Rotkreuz Switzerland

Tanz Centre for Research in Neurodegenerative Diseases University of Toronto Toronto ON Canada

Universitat Pompeu Fabra Barcelona Spain

Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health University of Wisconsin Madison Madison WI USA

Women's Brain Foundation Basel Switzerland

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